Background
Management of Muscle-Invasive Bladder Cancer (MIBC) includes both surgery and systemic therapy. Neoadjuvant, cisplatin-based combination chemotherapy has demonstrated improved pathologic complete response (pCR), event-free survival (EFS), and OS compared with radical cystectomy alone. Many patients still develop recurrence, including progression to metastasis. Novel strategies such as combining chemotherapy and immunotherapy in a neoadjuvant setting and consolidating response post cystectomy in the adjuvant setting may improve clinical outcomes. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. PD-L1 inhibition with durvalumab, in combination with a standard neoadjuvant regimen (Gemcitabine+Cisplatin [G+C]), may improve immune-mediated antitumor response and increase the rates of pathologic responses and long-term survival.

Methods
NIAGARA (NCT03732677) is a Phase 3, randomized, open-label, multicenter, global study that will enroll ~1050 patients randomized (1:1) to durvalumab and G+C combination (Arm 1) or G+C (Arm 2) as neoadjuvant chemotherapy prior to radical cystectomy. Following radical cystectomy and during adjuvant therapy, patients in Arm 1 will receive durvalumab monotherapy for 8 cycles (8months); patients in Arm 2 will receive no adjuvant treatment. Patients with resectable MIBC (clinical stage T2N0M0-T4aN0M0) with transitional cell histology planning to undergo a radical cystectomy will be included. Primary endpoints are pCR rates at time of cystectomy following neoadjuvant treatment and EFS. Secondary and exploratory endpoints include proportion of patients who achieve pathologic response <P2 (stages Pa, P1, and carcinoma in situ) at time of cystectomy following neoadjuvant treatment, EFS at 24 months, metastasis-free survival, proportion of patients who undergo cystectomy, and OS at 5 years. Safety, patient-reported outcomes, pharmacokinetics, immunogenicity, and biomarkers will also be assessed. Enrollment opened in Dec 2018.

A Phase 3, Randomized, Open-Label, Multicenter, Global Study of Efficacy and Safety of Neoadjuvant Durvalumab in Combination With Gemcitabine+Cisplatin Followed by Adjuvant Durvalumab Alone in Muscle-Invasive Bladder Cancer: NIAGARA